The elevation of systemic arterial pressure in hypertensives is associated with a multifaceted sequence of microvascular derangements which undermine basic integrated microcirculatory functions. To date, no direct link has been established between the diverse pathophysiogical mechanisms that have been related to the hypertensive syndrome - neurogenic, humoral, structural - and one of the fundamental problems of hypertension, i.e. the high propensity for cardiovascular complication (stroke, atherosclerosis, myocardial infarction, among others). We therefore have advanced a novel hypothesis which offers for the first time an opportunity to establish a unified conceptual framework for the accelerated trend towards organ pathology in hypertension. An increasing body of evidence at the biophysical, biochemical, cellular, microcirculatory and whole organ level indicates that leukocyte activation is associated with a modification of the arteriolar wall function, with organ malperfusion and with tissue damage in a wide range of cardiovascular complications, including those found in hypertensives. Our initial exploration of this situation on blood cells from spontaneously hypertensive rats showed that the leukocytes display abnormalities which include a more than 100% increase in circulating cell counts throughout the syndrome, spontaneous free radical formation by granulocytes and monocytes, spontaneous degranulation of lysosomes, abnormal F-actin formation and cell deformability, together with a depressed membrane surface adhesion. In salt sensitive Dahl hypertensive, but not in the salt resistant form, the leukocyte abnormalities closely mirror those seen in the spontaneous hypertensive rats. Accordingly, we propose to explore in detail the following aims: a) the exacerbation of microvascular imbalance during hypertension through the release of oxygen free radicals in vivo as manifest in several different models of hypertensive rats, b) the consequences of changes in leukocyte activation on whole organ resistance and arteriolar tone, c) the changes in biophysical and biochemical properties of leukocytes associated with particular cardiovascular complications, d) the impact of abnormal leukocyte behavior on their transport in the microcirculation of hypertensives. The above projects will offer an opportunity to establish a link between the respective factors leading to the elevated pressure in hypertensives and the high risk for cardiovascular complications and thus should provide the foundation for novel therapeutic interventions and the prospect for more rational prevention.